Flu vaccines from tabacco plants

Brian -  So my name is Brian Ward.  I'm a Professor at McGill University in infectious diseases and I'm serving as the Medical Officer for Medicago.  The platform that's used is a transient transfection in a tobacco plant.  What that means is that pretty much all of the cells of the leaves of young tobacco plant are infected transiently by a bacterium that's carrying a little bit of DNA that we instruct the bacterium to deliver to the plant cells.  As a non-plant biologist, one of the coolest things about this entire process to me was the fact that you get the bacteria into all of the plant cells by literally turning these young tobacco plants upside down in water and then sucking the air out of the plant with a vacuum.  It's called "Vacuum Agroinfiltration" but it's fantastic because what happens is when you suck hard enough on the root of a plant, the leaves collapse like sponges.  You submerge them in a bath of these bacterium and then when you release the vacuum, every cell in every leaf of the plant sucks the liquid in containing the bacteria and every plant cell is infected simultaneously.

Chris -   So you get little seedlings of tobacco plants which are making proteins from the genes that you've added with this bacterium.

Brian -   The bacterium contains the genetic information in a plasmid and that plasmid directs the production of the viral protein within the cytoplasm of the plant cell.  So that single viral protein then migrates to the surface of the plant cell and it auto assembles into these small virus-like particles that look from the outside like a virus, but have nothing on the inside.  They're empty.  They don't contain virus genetic material.

Chris -   But critically, they can behave as a virus in terms of their immunogenicity.  You can put them in, the body thinks they look like a virus so it makes an immune response against them.

Brian -   Yes, these virus-like particles essentially trick the body into believing that there's a viral infection and so, the body makes a response that it would typically make to a virus that's infecting them.  But in this case, it's just a response to the surface haemoglutanin protein, and so, you get the benefit without much of the risk.

Chris -   How do you get the virus-like particles out and not end up with the whole other plant glup going with it?

Brian -   So that's another really interesting thing that the company has done.  Initially, they did grind up the plant cells.  As it turns out, these virus-like particles collect between the cell wall that surrounds each plant cell and the outside membrane of the plant cell.  In these pockets essentially that contain large numbers of virus-like particles.  The cell wall can be digested with enzymes that are directed against plant wall but not plant membrane.  As a result, you can put the plant mass, just slightly ground up plant material, into a vat with enzymes and the cell walls are digested away because the virus-like particles are between the cell wall and the outside membrane of the plant cell, they are simply released into the liquid in which you're doing the digestion, making the purification very easy.

Chris -   Now when we make flu vaccines in egg, you get roughly three doses per egg.  So how many doses do you get per tobacco plant?

Brian -   It's highly variable.  The production facility in North Carolina works with batches of about 15,000 plants.  15 000 plants translate into about 30 kg of plant material - so it looks green - and then that green material can yield about 5 million doses of vaccine.

Chris -   So quite a bit and presumably very fast to make.

Brian -   That's one of the huge advantages of this platform is that the tobacco plants are young, healthy, growing, they're transfected.  When they're harvested between 5 and 8 days later depending on how much sun there is, they look perfectly healthy, and so, you harvest and then process so that the cycle of production is actually very, very fast.

Chris -   No risk of people getting hooked on flu vaccines?

Brian -   I don't think so.  No risk of people getting hooked on flu vaccines.

Chris -   But being more serious, when you put the vaccine material into a clinical setting, what have you done with this so far?  Has this just gone through animals?  Have you just done this in terms of demonstration?  Where are you in the sort of approval process?

Brian -   So far, the company has done the standard work pre-clinical which means animal studies and toxicity studies, and in fact, two of the products have gone into human trials.  One of the products, the H5 monovalent vaccine has gone forward into a phase II study.

Chris -    It's against bird flu - H5 N1.

Brian -   This is against the bird flu.  So that's the product that's furthest advanced.  The total number of people involved in those studies is about 300 so far - phase I and phase II, and the seasonal H1 vaccine which is again a monovalent vaccine that targets the circulating H1 virus now, that's gone into 100 people to date.

Chris -   Have you actually got to the stage where those people have been challenged with flu so you know that they're making a protective response?

Brian -   So, one of the options for testing a flu vaccine is to do a human challenge study, but we haven't done that yet.  Right now in phase I and phase II trials, what you're looking for is safety, how well the vaccines are tolerated, and what kind of immune response they make.  And so far, these vaccines are very well tolerated, very similar to the kinds of responses that you get from a standard trivalent vaccine.  But they also elicit really quite strong immune responses.  The H1 vaccine certainly meets all of the criteria for licensure for the trivalent vaccines.  So clearly, that's the next step for the company, to actually move from the monovalent H1 vaccine, to incorporate an H3 containing vaccine, and a B type virus to make a trivalent virus-like particle vaccine made in plants.

Chris -   And the timeline for that?

Brian -   Can I say soon and get away with it?  I think that there's a hope that by the end of 2011, that there will be a candidate trivalent vaccine that can be tested at least pre-clinically.

Chris -   What about costs?

Brian -   That's one of the huge advantages of this platform.  Using plants as the bioreactors instead of stainless steel vats in a high production facility allows the cost of goods to be considerably lower.  And so, these vaccines can be produced for less than the standard vaccines that are produced in eggs.  Furthermore, the facility itself, because it's not based on incubation of eggs and supply chain of high quality eggs, and so on, is also considerably less expensive than the investment in an egg based facility.